Processes For The Preparation Of 2,5-Dihydroxybenzenesulfonic Acid Salts

ABSTRACT

Processes for the preparation of 2,5-dihydroxybenzenesulfonic acid salts of formula (I) and a crystalline form of potassium 2,5 2,5-dihydroxybenzenesulfonic acid are provided.

INCORPORATION BY REFERENCE

This application claims the benefit of priority of Indian ProvisionalPatent Application No. 21/CHE/2008, filed on Jan. 3, 2008.

The foregoing application, and all documents cited therein or duringtheir prosecution (“application cited documents”) and all documentscited or referenced in the application cited documents, and alldocuments cited or referenced herein (“herein cited documents”), and alldocuments cited or referenced in herein cited documents, together withany manufacturer's instructions, descriptions, product specifications,and product sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.

FIELD OF THE INVENTION

Processes for the preparation of 2,5-dihydroxybenzenesulfonic acid saltsof the formula (I) are described:

The compounds of the formula (I), wherein X is at least one cation, andm and n are independently 1 or 2, are known as salts of2,5-dihydroxybenzenesulfonic acid or hydroquinonesulfonic acid.

BACKGROUND OF THE INVENTION

2,5-Dihydroxybenzenesulfonic acid derivatives and specifically calciumdobesilate, ethamsylate and persilate are known in the art as activeagents for the treatment of male sexual dysfunction and other vasculardisorders of endothelial origin, both alone and in combination withother agents. U.S. Pat. No. 6,147,112 describes a method for the use of2,5-dihydroxybenzenesulfonic acid derivatives, preferably calciumdobesilate, ethamsylate and persilate.

Calcium dobesilate or hydroquinone calcium sulfonate, with the chemicalname 2,5-dihydroxybenzenesulfonic acid calcium salt, is being sold asDexium (Delalande) and Doxium (Carrion), and a process for itspreparation is described in U.S. Pat. No. 3,509,207.

The potassium salt of 2,5-dihydroxybenzenesulfonic acid, formula (Ia),is also an important compound.

Combinations of active substances comprising a2,5-dihydroxybenzenesulfonic acid compound including potassium2,5-dihydroxybenzenesulfonate are disclosed in International ApplicationPublication No. WO 2005/013962. Compositions and methods of use for2,5-dihydroxybenzenesulfonic acid compounds and their pharmaceuticallyacceptable salts, including potassium 2,5-dihydroxybenzenesulfonate, arediscussed in U.S. Patent Publication No. 20070149618.

In view of the importance of the potassium salt of2,5-dihydroxybenzenesulfonic acid, it is desirable to develop a processfor its manufacture by a simple method with improved yield, purity andstability.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a simple, commerciallyviable, and industrially scalable process for the preparation ofcompounds of the formula (I), which involves simple isolation of theproduct and work-up.

Accordingly, the present invention provides a process for thepreparation of compounds of formula (I)

wherein X is at least one cation, and m and n are independently 1 or 2,said process comprising:

-   -   i) sulfonation of hydroquinone of formula (II) in the presence        or absence of solvent, to a compound of formula (III);

-   -   ii) treating the compound of formula (III) with salts of an        organic acid in a suitable solvent; and    -   iii) precipitating the product of formula (I).

It is a further object of the invention to provide a process for theremoval of inorganics, if formed, in the process of the preparation ofcompounds of formula (I), which process comprises:

-   -   1. dissolving the crude potassium salt of        2,5-dihydroxybenzenesulfonic acid in water;    -   2. adding a water-miscible solvent to precipitate the        inorganics; and    -   3. isolating the product of formula (I).

In certain embodiments, the invention relates to a process for thepreparation of compounds of formula (I)

wherein X is at least one cation, and m and n are independently 1 or 2,said process comprising: (i) sulfonation of hydroquinone of formula (II)in presence or absence of solvent, to provide a compound of formula(III):

(ii) treating the compound of formula (III) with salts of organic acidin a suitable solvent; and (iii) precipitating the product of formula(I).

In certain embodiments, X is selected from the group consisting oflithium, sodium, potassium, rubidium, cesium, beryllium, magnesium orcalcium. In a particular embodiment, X is potassium; m is 1; and n is 1.In some embodiments, the salt of organic acid used is potassium2-ethylhexanoate. In another embodiment, the salt of organic acid usedis potassium 2-ethylhexanoate; X is potassium; in is 1; and n is 1.

In some embodiments, the salt of organic acid used is calcium2-ethylhexanoate. In certain embodiments, the salt of organic acid usedis calcium 2-ethylhexanoate; X is calcium; m is 1; and n is 2.

In another embodiment, X is selected from the group consisting of[NH_(4-p)R_(p)]⁺; wherein p at each occurrence is independently selectedfrom an integer from 0 to 4; and each R is independently a C₁-C₄ alkylgroup, a C₄-C₇ cycloalkyl group, aryl group, or heteroaryl group. In aparticular embodiment, X is selected from the group consisting ofdiethylamine group [(C₂H₅)₂NH₂]⁺, piperazine and pyridine.

In some embodiments, the sulfonation is carried out using sulfuric acid,fuming sulfuric acid, or a halosufonic acid. In a particular embodiment,the sulfonation is carried out using sulfuric acid.

In some embodiments, the solvent used in (i) is selected from the groupconsisting of C₅-C₁₂ alkanes, C₅-C₁₂ cycloalkanes, and C₁-C₁₂haloalkanes; or mixtures thereof. In certain embodiments, the solventused in (i) is selected from the group consisting of n-heptane,n-hexane, n-octane, dichloromethane and 1,2-dichloroethane.

In some embodiments, the solvent used in (ii) is selected from the groupconsisting of C₅-C₁₂ alkanes, C₅-C₁₂ cycloalkanes, C₁-C₁₂ haloalkanes,C₂-C₈ alkyl acetates, C₂-C₁₂ alkyl ethers, C₅-C₁₀ cycloalkyl ethers andmixtures thereof. In certain embodiments, the solvent used in (ii) isselected from the group consisting of ethyl acetate, n-heptane, andn-butyl acetate.

In other embodiments, the invention relates to a crystalline form ofpotassium 2,5-dihydroxybenzenesulfonic acid having characteristic 2θvalues of 8.8, 13.7, 15.6, 18.9, 21.4, 26.8, 27.7 and 30.3 (±1).

In some embodiments, the invention relates to a process for thepreparation of a compound of formula (I)

wherein X is potassium, and m and n are each 1, said process comprising:(i) sulfonation of hydroquinone of formula (II) using sulfuric acid toprovide a compound of formula (III):

(ii) treating the compound of formula (III) with potassium2-ethylhexanoate; and (iii) precipitating the product of formula (I).

In yet other embodiments, the invention relates to a process for theremoval of inorganics formed in the preparation of compounds of formula(I), which process comprises the steps of (i) dissolving the crudecompound of formula (I) in water; (ii) adding a water-miscible solventselected from the group consisting of alcohols, ketones, and nitriles toprecipitate the inorganics; and (iii) isolating the product of formula(I).

It is noted that in this disclosure and particularly in the claimsand/or paragraphs, terms such as “comprises”, “comprised”, “comprising”and the like can have the meaning attributed to it in U.S. Patent law;e.g., they can mean “includes”, “included”, “including”, and the like;and that terms such as “consisting essentially of and “consistsessentially of have the meaning ascribed to them in U.S. Patent law,e.g., they allow for elements not explicitly recited, but excludeelements that are found in the prior art or that affect a basic or novelcharacteristic of the invention.

These and other embodiments are disclosed or are obvious from andencompassed by, the following Detailed Description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description, given by way of example, but notintended to limit the invention solely to the specific embodimentsdescribed, may be further understood in conjunction with theaccompanying drawings, in which;

FIG. 1: PXRD pattern of potassium 2,5-dihydroxybenzenesulfonic acid(Example 6).

FIG. 2: PXRD pattern of potassium 2,5-dihydroxybenzenesulfonic acid(Example 7)

DETAILED DESCRIPTION

For the purposes of this application, unless otherwise stated in theapplication, the following terms have the terminology indicated below.

Alkyl refers to both straight and branched carbon chains; references toindividual alkyl groups are specific for the straight chain (e.g.,butyl=n-butyl). In one embodiment of alkyl, the number of carbon atomsis 1-8, in another embodiment of alkyl, the number of carbon atoms is1-4 carbon atoms and in yet another embodiment of alkyl, the number ofcarbon atoms is 1-2 carbon atoms.

Aryl refers to a C₆-C₁₄ aromatic ring structure. In one embodiment ofaryl, the moiety is phenyl, naphthyl, and anthracenyl. In anotherembodiment of aryl, the moiety is phenyl. The aryl group can beoptionally substituted with one or more substituents.

Heteroaryl refers to a C₅-C₁₄ aromatic ring structure, wherein at leastone atom other than carbon is present in the aromatic ring structure. Inone embodiment of heteroaryl, the moiety is pyridyl. In anotherembodiment of heteroaryl, the moiety is pyrimidinyl. Other examples ofheteroaryl moieties include, for example, thiophenyl, pyrazinyl,furanyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, quinolinyl, benzothiophenyl, benzimidazolinyl, benzofuranyl,benzisoxazolyl, and the like. The heteroaryl group can be optionallysubstituted with one or more substituents.

Cyclo as a prefix (e.g., cycloalkyl) refers to a saturated orunsaturated cyclic ring structure having from three to eight carbonatoms in the ring, the scope of which is intended to be separate anddistinct from the definition of aryl above. In one embodiment of cyclo,the range of ring sizes is 4-7 carbon atoms; in another embodiment ofcyclo the range of ring sizes is 3-4. Other ranges of carbon numbers arealso contemplated depending on the location of the cyclo-moiety on themolecule.

Alcohol refers to alkyl and cycloalkyl groups attached to an —OH group,and may include, by way of non-limiting example, isopropyl alcohol,ethyl alcohol, cyclohexyl alcohol and the like.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts andsolvates of the compounds), such as those which may exist due toasymmetric carbon atoms on various substituents, including enantiomericforms, rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention.

When any variable (e.g., aryl, heteroaryl, R, X, m, n, etc.) occurs morethan once in any constituent or formula, the definition thereof on eachoccurrence is independent of its definition at every other occurrence.

This application contemplates all acceptable acid or base salt forms ofthe compounds, where applicable. The term “acid” contemplates allinorganic or organic acids.

Inorganic acids include mineral acids such as hydrohalic acids, such ashydrobromic and hydrochloric acids, sulfuric acids, phosphoric acids andnitric acids.

Organic acids include all aliphatic, alicyclic and aromatic carboxylicacids, dicarboxylic acids, tricarboxylic acids and fatty acids.Preferred acids are straight chain or branched, saturated or unsaturatedC₁-C₂₀ aliphatic carboxylic acids, which are optionally substituted byhalogen or by hydroxyl groups, or C₆-C₁₂ aromatic carboxylic acids.Examples of such acids are carbonic acid, formic acid, fumaric acid,acetic acid, propionic acid, isopropionic acid, valeric acid, a-hydroxyacids, such as glycolic acid and lactic acid, chloroacetic acid, benzoicacid, methanesulfonic acid, and salicylic acid. Examples of dicarboxylicacids include oxalic acid, malic acid, succinic acid, tataric acid andmaleic acid. An example of a tricarboxylic acid is citric acid. Fattyacids include all saturated or unsaturated aliphatic or aromaticcarboxylic acids having 4 to 24 carbon atoms. Examples include butyricacid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid,stearic acid, oleic acid, linoleic acid, linolenic acid, andphenylsteric acid. Other acids include gluconic acid, glycoheptonic acidand lactobionic acid.

The term “base” contemplates all inorganic or organic bases. Such basesinclude, for example, the alkali metal and alkaline earth metal salts,such as the lithium, sodium, potassium, magnesium or calcium salts.Organic bases include the common hydrocarbyl and heterocyclic aminesalts, which include, for example, the diethylamino, morpholine andpiperidine salts.

The term “cation” contemplates all organic and inorganic positivelycharged ions. The cation in the compounds of formula (I) may include, byway of non-limiting example, those described in “Handbook ofPharmaceutical Salts: Properties, Selections and Use”, Stahl, H. andWermuth, C., ed., Verlag Helvetica Chemica Acta, Zurich, Wiley-VCH,2002.

The term “organic cation” contemplates all positively charged organicions. Exemplary organic cations include alkyl substituted ammoniumcations, cycloalkyl substituted ammonium cations, unsubstituted ammoniumcations, primary, secondary and tertiary amines, alkyl amines,cycloalkyl amines, aryl amines, N,N′-dibenzylethylenediamine and thelike;

The term “inorganic cation” refers to a positively charged metal ion.Exemplary inorganic cations include Group I and Group II metal cations,such as, for example, lithium, sodium, potassium, rubidium, cesium,beryllium, magnesium, calcium and the like.

Water-miscible organic solvents include, by way of non-limiting example,ketones such as, for example, acetone; alcohols, such as, for example,ethyl alcohol or isopropyl alcohol; and nitriles, such as, for example,acetonitrile. Other water-miscible solvents are apparent to the skilledartisan, and may be further discussed, for example, in “The Chemist'sCompanion: A Handbook of Practical Data, Techniques, and References,”Gordon, A. J. and Ford, R. A., John Wiley and Sons, New York, 1972.

Reagents for sulfonation may be selected from any employed in the art,including, by way of non-limiting example, sulfuric acid, fumingsulfuric acid, and halosulfonic acids (such as fluoro- orchloro-sulfonic acid).

The acids, bases, reagents, additives, temperatures, and solvents usedin the invention will be apparent to those of ordinary skill in the art(e.g., Comprehensive Organic Transformations, R. C. Larock, VCHPublishers (1989); Vogel's Textbook of Practical Organic Chemistry(5^(th) Edition), Furniss et al., Longman Scientific & Technical (1989);Protective Groups in Organic Synthesis (3^(rd) Edition), Greene & Wuts,Wiley Interscience (1999); March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure (6^(th) Edition), March & Smith,Wiley, (2007); Advanced Organic Chemistry (Part A—Structure andMechanisms—4^(th) Edition), Carey & Sundberg, Springer Science (2000);Advanced Organic Chemistry (Part B—Reaction and Synthesis—4^(th)Edition), Carey & Sundberg, Springer Science (2001); StrategicApplications of Named Reactions in Organic Synthesis, Kurti and Czako,Academic Press (2005)).

Compounds of the invention may be present in the form of solvates,particularly in the form of hydrates.

It will be appreciated by the skilled artisan that the terminology forcompositions and structures referred to herein encompasses thosecompositions and structures known in the art.

In one embodiment, the present invention provides a process for thepreparation of compounds of formula (I), wherein X is potassium, and mand n are each 1, which comprises:

-   -   i) treating the compound of formula (III) with potassium        2-ethylhexanoate in an organic solvent; and    -   ii) isolating the product of formula (I).

In another embodiment, the cation is an inorganic cation.

In another embodiment, the cation is an organic cation.

In another embodiment, the cation is an inorganic cation selected fromthe group consisting of sodium, potassium, lithium, calcium ormagnesium.

In another embodiment, the cation is an organic cation selected from thegroup consisting of [NH_(4-p)R_(p)]⁺; wherein p at each occurrence isindependently selected from an integer from 0 to 4; and each R isindependently a C₁-C₄ alkyl group, a C₄-C₇ cycloalkyl group, aryl group,or heteroaryl group.

In another embodiment of the invention, the cation is an organic cationselected from the group consisting of diethylamine groups [(C₂H₅)₂NH₂]⁺,piperazine or pyridine.

In another embodiment of the invention, the compound of formula (I) ispotassium 2,5-dihydroxybenzene sufonic acid (potassium dobesilate).

In another embodiment of the invention, the compound of formula (I) iscalcium 2,5-dihydroxybenzene sufonic acid (calcium dobesilate).

In another embodiment of the invention, the compound of formula (I) ismagnesium 2,5-dihydroxybenzene sufonic acid (magnesium dobesilate).

In another embodiment of the invention, the compound of formula (I) isdiethylamine 2,5-dihydroxybenzene sufonic acid (ethamsylate).

In another embodiment, the present invention provides for thepreparation of compounds of formula (I), wherein the solvent used instep i) is selected from C₅-C₁₂ alkanes, C₅-C₁₂ cycloalkanes, and C₁-C₁₂haloalkanes, or mixtures thereof.

In a preferred embodiment, the solvent used in (i) is selected fromalkanes such as, for example, n-hexane, n-heptane, n-octane,cyclohexane; or chlorinated solvents such as dichloromethane and1,2-dichloroethane.

In a further preferred embodiment, the solvent used in (i) is n-heptane.

In another embodiment, the present invention provides for thepreparation of compounds of formula (I), wherein the solvent used in(ii) is selected from C₅-C₁₂ alkanes, C₅-C₁₂ cycloalkanes, C₁-C₁₂haloalkanes, C₂-C₈ alkyl acetates, C₂-C₁₂ alkyl ethers, and C₅-C₁₀cyclic alkyl ethers (e.g.-tetrahydrofuran, dioxane, and the like, ormixtures thereof.

In yet another embodiment, the solvent used in (ii) is selected fromethyl acetate, n-heptane, n-butyl acetate and the like or mixturesthereof.

In another embodiment, the invention provides a process for making acrystalline form of potassium 2,5-dihydroxybenzenesulfonic acid havingcharacteristic 2θ values of 8.8, 13.7, 15.6, 18.9, 21.4, 26.8, 27.7 and30.3 (±1).

In another embodiment, salts of organic acids used in (ii) are selectedfrom group I or II metal salts.

In another embodiment, salts of organic acids used in (ii) are selectedfrom amine salts.

In a further embodiment, organic acids used in (ii) are selected fromC₁-C₁₀ straight chain or branched carbocyclic acids.

In yet another embodiment, salts of organic acids used in (ii) areselected from potassium 2-ethylhexanoate and the like. It isadvantageous to employ potassium 2-ethylhexanoate in the precipitationof a compound of formula (I), which in turn results in easy isolation ofthe formed product. The combination of a potassium salt of an organicacid and suitable reaction solvent renders the formation of a potassiumsalt to of 2,5-dihydroxybenzenesulfonic acid as a precipitate, therebyavoiding the use of co-solvents, precipitants, or complete evaporationfor precipitation of product, making the process industrially viable forscale-up.

In a further embodiment, the water-miscible organic solvent used in (ii)is selected from acetone, alcohols such as, for example, isopropylalcohol (IPA), and the like or mixtures thereof.

In further embodiments, the process described herein may be convenientlyfollowed for the preparation of salts other than the potassium salt of2,5-dihydroxybenzenesulfonic acid by using suitable salts of an organicacid source. For example, sodium 2-ethylhexanoate or calcium2-ethylhexanoate could be used in the preparation of sodium or calciumsalts of 2,5-dihydroxybenzenesulfonic acids, respectively.

The use of sodium dithionate in the reaction process yielded thecompound of formula (I) with an improved color. Whenever required, theproduct formed is recrystallized or washed with suitable solvents tohave improved quality of the final product with lesser impurities,thereby making it more suitable for pharmaceutical formulation.

The invention will be further described by the following examples, whichare provided by way of illustration only and should not be construed tolimit the scope of the invention.

Process for the Preparation of potassium salt of2,5-dihydroxybenzenesulfonic acid EXAMPLE 1

Hydroquinone (25 g, 0.2270 mol) n-heptane (75 mL) was taken in a roundbottom flask, after cooling the flask to about 10-15° C., sulfuric acid(36 N, 22.2 g) was added dropwise at the same temperature and stirringcontinued further for about 10-15 min. Temperature was slowly raised to50-55° C. then stirring continued for 3 h. The reaction mass was thencooled to 25-35° C. and ethyl acetate (250 mL) added to dissolve thesolid formed. A solution of potassium 2-ethylhexanoate (41.3 g, 0.2265mol) in ethyl acetate (250 mL) was added slowly. The reaction wasfurther stirred for an hour. The precipitated crude solid was filtered,washed with ethyl acetate.

EXAMPLE 2

Hydroquinone (20 g, 0.1816 mol) and n-heptane (60 mL) was taken in around bottom flask, after cooling the flask to about 10-15° C., sulfuricacid (36 N, 17.8 g) was added dropwise at the same temperature andstirring continued further for about 10-15 min. The temperature wasslowly raised to 50-60° C. then stirred for 3-8 h. The reaction mass wasthen cooled to 25-35° C., n-heptane was decanted and ethyl acetate (200mL) added to dissolve the solid formed. A solution of potassium2-ethylhexanoate (36.4 g, 0.1996 mol) in ethyl acetate (200 mL) wasadded slowly. The reaction was further stirred for an hour. Theprecipitated crude solid was filtered, washed with ethyl acetate to give40 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.

EXAMPLE 3

Hydroquinone (10 g, 0.09 mol) was taken in a round bottom flask, aftercooling the flask to about 10-15° C., sulfuric acid (36 N, 8.9 g) wasadded dropwise at the same temperature and stirring continued furtherfor about 10-15 min. Temperature was slowly raised to 50-60° C. thenstirred for 3-8 h. The reaction mass was then cooled to 25-35° C. andethyl acetate (100 mL) added to dissolve the solid formed. A solution ofpotassium 2-ethylhexanoate (18.2 g, 0.099 mol) in ethyl acetate (100 mL)was added slowly. The reaction was further stirred for an hour. Theprecipitated crude solid was filtered, washed with ethyl acetate to give16 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.

EXAMPLE 4

Hydroquinone (10 g, 0.09 mol) and dichloromethane (30 mL), was taken ina round bottom flask, after cooling the flask to about 10-15° C.,sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperatureand stirring continued further for about 10-15 min. Temperature wasslowly raised to 30-40° C. then stirred for 1-2 h. The reaction mass wasthen cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolvethe solid formed. A solution of potassium 2-ethylhexanoate (18.2 g,0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction wasfurther stirred for an hour. The precipitated crude solid was filtered,washed with ethyl acetate to give 16 g of 2,5-dihydroxybenzenesulfonicacid potassium salt.

EXAMPLE 5

Hydroquinone (10 g, 0.09 mol) and 1,2-dichloroethane (30 mL) was takenin a round bottom flask, after cooling the flask to about 10-15° C.,sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperatureand stirring continued further for about 10-15 min. Temperature wasslowly raised to 40° C. then stirred for 3-8 h. The reaction mass wasthen cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolvethe solid formed. A solution of potassium 2-ethylhexanoate (18.2 g,0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction wasfurther stirred for an hour. The precipitated crude solid was filtered,washed with ethyl acetate to give 18 g of 2,5-dihydroxybenzenesulfonicacid potassium salt.

EXAMPLE 6

Hydroquinone (20 g, 0.186 mol) in n-heptane (100 mL) was taken in around bottom flask, after cooling the flask to 10-15° C., sulfuric acid(36 N, 17.8 g) was added dropwise at the same temperature and stirringcontinued further for about 10-15 min. Temperature was slowly raised to53-58° C. then stirring continued for 10 h. The reaction mass was thencooled to 25-35° C. and ethyl acetate (200 mL) added to dissolve thesolid formed. A solution of potassium 2-ethylhexanoate (36.46 g, 0.1996mol) in ethyl acetate (200 mL) was added slowly. The reaction wasfurther stirred for about an hour. The precipitated crude solid wasfiltered, washed with ethyl acetate. The crude solid obtained was thenslurry washed with ethyl acetate. The crude product was dissolved in 2.5V of dimethylacetamide and 0.5 V methyl isobutyl ketone, filtered andwas added 10-15 V of acetonitrile to the filterate to precipitate theproduct. After stirring for 15 min., the product was filtered, washedwith acetonitrile. The product obtained was dissolved in water (3 V) andisopropyl alcohol (5 V) was added. The reaction mixture was filtered;followed by the addition of further 5 V of isopropyl to alcohol. Thereaction mass was evaporated under reduced pressure and the total volumewas reduced to 1 V. To the reaction mixture was added 15 V of ethylacetate and then was reduced to 10 V by distilling under reducedpressure to get the pure product. The product was filtered, washed withethyl acetate and dried. The final product obtained was crystalline innature and the corresponding PXRD pattern is shown in FIG. 1 and TableA. Yield 18 g.

Table A shows the PXRD values of potassium 2,5-dihydroxybenzenesulfonicacid obtained following Example 6. The corresponding PXRD pattern isgiven in FIG. 1.

TABLE A Angle d value Intensity % 2-Theta ° Angstrom % 8.884 9.9453 90.012.973 6.8188 3.0 13.766 6.4278 20.1 15.619 5.6689 76.6 17.129 5.172427.1 17.784 4.9835 50.3 18.997 4.6680 49.2 19.983 4.4398 7.7 20.1664.3998 8.4 20.719 4.2837 13.7 21.400 4.1488 51.3 21.474 4.1346 58.222.149 4.0103 18.9 22.733 3.9085 15.7 22.814 3.8948 10.8 23.009 3.86219.4 23.816 3.7331 2.9 24.910 3.5716 17.5 26.099 3.4116 9.4 26.794 3.3246100.0 26.875 3.3148 52.7 27.081 3.2900 10.9 27.693 3.2187 32.5 28.4703.1326 4.6 28.686 3.1095 7.3 28.896 3.0874 4.1 30.016 2.9747 7.9 30.3742.9404 33.8 30.457 2.9326 17.7 31.233 2.8614 5.3 31.669 2.8230 4.032.094 2.7867 5.8 32.702 2.7362 3.5 33.415 2.6794 13.2 33.519 2.6714 7.534.317 2.6110 9.3 34.414 2.6039 5.5 34.653 2.5865 2.6 35.139 2.5518 2.635.681 2.5143 7.6 35.868 2.5016 6.3 35.956 2.4957 41.8 36.042 2.490021.4 36.797 2.4406 6.0 36.895 2.4343 3.4 37.261 2.4112 16.7 37.3502.4057 8.8 38.050 2.3630 12.4 38.148 2.3572 7.0 38.264 2.3503 3.9 38.4942.3368 9.7 38.605 2.3303 5.3 38.964 2.3097 9.1 39.080 2.3031 5.3 39.5782.2753 5.7 39.683 2.2694 3.4 39.914 2.2569 4.1 40.023 2.2510 2.8 40.5632.2222 5.0 40.679 2.2162 3.1 41.254 2.1866 2.0 41.755 2.1615 3.2 41.8532.1567 2.2 42.215 2.1390 5.2 42.319 2.1340 3.2 42.535 2.1236 13.5 42.6452.1185 7.6 43.529 2.0774 4.6 43.655 2.0717 3.2

Purification of potassium salt of 2,5-dihydroxybenzenesulfonic acidEXAMPLE 7

Crude 2,5-dihydroxybenzenesulfonic acid potassium salt (50 g) was addedin water (150 mL) at 25-30° C. and acetone (500 mL), then stirred for15-30 min. and filtered. The filtrate was concentrated to 50-75 mL. Theexcess water present in the reaction mixture was again removed by adding2×250 mL of isopropyl alcohol and distilled upto 50-75 mL under vacuum.To the residue was added 750 mL of ethyl acetate and distilled up to250-300 mL and the solid formed was filtered and dried to give 25 g ofproduct with assay greater than 98%.

The compound of formula (I) obtained is crystalline in nature asrevealed from the Powder X-ray diffraction (PXRD) data. Table B showsthe PXRD values of potassium 2,5-dihydroxybenzenesulfonic acid obtainedfollowing E xample 7. The corresponding PXRD pattern is shown in FIG. 2.

TABLE B Angle d value Intensity % 2-Theta Angstrom % 8.294 10.6515 20.78.840 9.9950 25.4 12.940 6.8361 2.5 13.250 6.6765 3.9 13.717 6.4505 18.515.573 5.6857 100.0 17.078 5.1877 19.7 17.732 4.9979 12.4 18.940 4.681837.0 19.279 4.6002 5.2 19.935 4.4504 7.3 20.125 4.4086 7.2 20.676 4.292412.2 21.344 4.1596 58.3 21.422 4.1445 58.5 22.103 4.0184 19.0 22.6913.9156 10.7 22.756 3.9045 9.7 22.969 3.8688 7.3 24.054 3.6967 3.4 24.8733.5768 16.1 25.074 3.5486 2.7 25.454 3.4965 2.1 26.076 3.4145 8.6 26.7413.3311 23.3 27.028 3.2963 15.2 27.648 3.2238 34.9 27.711 3.2167 18.228.419 3.1381 3.6 28.631 3.1153 6.8 28.847 3.0925 3.3 29.975 2.9786 7.430.340 2.9437 26.6 30.407 2.9373 14.5 31.263 2.8588 7.3 31.637 2.82582.5 32.067 2.7889 6.2 32.962 2.7153 2.3 33.371 2.6829 9.2 33.484 2.67415.4 33.646 2.6616 2.3 34.285 2.6134 9.6 34.372 2.6070 5.3 34.588 2.59121.9 35.108 2.5540 2.1 35.622 2.5183 5.6 35.710 2.5123 3.2 35.812 2.50544.4 35.902 2.4993 7.6 35.985 2.4938 3.8 36.099 2.4861 3.3 36.743 2.44405.2 36.850 2.4372 3.9 37.204 2.4148 12.5 37.320 2.4075 7.2 38.005 2.365714.2 38.113 2.3593 8.0 38.225 2.3526 4.3 38.447 2.3395 5.1 38.555 2.33323.4 38.918 2.3123 9.9 39.018 2.3066 5.3 39.530 2.2779 3.3 39.636 2.27212.5 39.892 2.2581 3.2 39.990 2.2528 2.8 40.532 2.2239 4.5 41.152 2.19181.9 41.696 2.1644 2.8 41.810 2.1588 2.2 42.176 2.1409 4.9 42.288 2.13553.4 42.475 2.1265 10.9 42.597 2.1207 5.6 42.814 2.1105 2.8 43.479 2.07975.5 43.663 2.0714 3.3 43.923 2.0597 2.2 44.090 2.0523 1.3

EXAMPLE 8

To crude 2,5-dihydroxybenzenesulfonic acid potassium salt (50 g) wasadded water (150 mL) at 25-30° C. and isopropyl alcohol (500 mL) and wasstirred for 15-30 min. and filtered. The filtrate was concentrated up to50-75 mL. To the residue was added 750 mL of ethyl acetate and distilledup to 250-300 mL. The solid formed was filtered and dried to give 22 gof product with assay greater than 98%.

Having thus described in detail preferred embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

1.-15. (canceled)
 16. A crystalline form of potassium2,5-dihydroxybenzenesulfonic acid having characteristic 2θ values of8.8, 13.7, 15.6, 18.9, 21.4, 26.8, 27.7 and 30.3 (±1). 17.-18.(canceled)
 19. A crystalline form of potassium2,5-dihydroxybenzenesulfonic acid having the PXRD pattern substantiallyas shown in FIG.
 1. 20. A crystalline form of potassium2,5-dihydroxybenzenesulfonic acid having the PXRD pattern substantiallyas show in FIG.
 2. 21. The crystalline form of potassium2,5-dihydroxybenzenesulfonic acid of claim 19 crystallized from awater/solvent mixture.
 22. The crystalline form of potassium2,5-dihydroxybenzenesulfonic acid of claim 21 wherein the solvent isisopropyl alcohol.
 23. The crystalline form of potassium2,5-dihydroxybenzenesulfonic acid of claim 22 precipitated using ethylacetate.
 24. The crystalline form of potassium2,5-dihydroxybenzenesulfonic acid of claim 20 crystallized from awater/solvent mixture.
 25. The crystalline form of potassium2,5-dihydroxybenzenesulfonic acid of claim 24 wherein the solvent isacetone.
 26. The crystalline form of potassium2,5-dihydroxybenzenesulfonic acid of claim 25 precipitated using ethylacetate.